Human immunodeficiency virus (HIV) causes a variety of clinical manifestations such as opportunistic infection, Kaposi's sarcoma, wasting syndrome, and neurological defects. The main goal of this project is to determine the role of variation in viral sequences in causing these different syndromes. In the past year brain samples from a prospective clinical study on HIV dementia were used to identify significant sequences in HIV envelope C2 and V3 regions which differed in demented and nondemented AIDS patients. Sequences from both groups were also cloned in infectious plasmids and were found to be macrophage-tropic in all cases. These results are consistent with the interpretation that most HIV strains present in brain are macrophage-tropic strains which infect brain microglial cells, but HIV dementia appears to correlate with the appearance of a unique subset of macrophage-tropic viruses which cause dementia via as yet unknown mechanisms. More recent studies have focussed on in vitro infection of human macrophages by HIV strains which vary in replication levels in macrophages. This variation was found to occur only in macrophages and not in lymphocytes, and it correlated with sequence differences in the envelope V1 and V2 regions. Immunostaining of virus-positive cells at various times after infection showed that high replication levels were due to viral spread in the macrophages whereas low replication levels were seen in viruses which were unable to spread to new cells after initial infection. These two replication phenotypes have been seen in primary AIDS patient HIV isolates and might play different roles in in vivo pathogenesis.